Luteolin use in Integrated Stress Response: insight from a case of EIF2AK2-related dystonia

This study presents the first reported case of a 3-year-old child with EIF2AK2-related dystonia treated with adjunctive luteolin supplementation. EIF2AK2-related dystonia, characterized by exacerbations during infections, is associated with disruptions in the integrated stress response (ISR). The ISR, a cellular signaling pathway activated in response to stress, culminates in the phosphorylation of eIF2α, which modulates protein synthesis and can induce cell death. Pathogenic variants in EIF2AK2 disrupt this pathway, contributing to the development of dystonia. Luteolin, a flavonoid possessing anti-inflammatory and neuroprotective properties, was hypothesized to modulate the ISR, thereby attenuating infection-induced dystonic exacerbations. The patient, exhibiting early-onset dystonia with clinical worsening during febrile episodes, harbored a de novo pathogenic variant in EIF2AK2. Following initial clinical improvement with trihexyphenidyl, adjunctive luteolin therapy was initiated, resulting in further clinical enhancements. Quantitative assessment using dystonia rating scales (UDRS, MSS, DSS) demonstrated sustained improvement, characterized by a reduction in the severity and frequency of infection-triggered relapses. The proposed mechanism of action involves luteolin disrupting the PACT-PKR interaction, a critical step in ISR activation, thus preventing excessive eIF2α phosphorylation and subsequent cellular dysfunction. This mechanism, supported by in vitro studies utilizing relevant disease models, suggests luteolin's potential to stabilize cellular homeostasis under stress. This case report indicates that luteolin may serve as a promising adjunctive therapeutic strategy for patients with infection-sensitive dystonic phenotypes, such as EIF2AK2-related dystonia. Further randomized controlled trials are warranted to validate these findings and establish the optimal dosing regimen and long-term safety profile of luteolin in vivo.